Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48].
Further experiments based on the injection of a PP2A inhibitor in the rat hippocampus demon- strated tau hyper-phosphorylation, and learning and memory deficits [49, 50].
Studies in transgenic mice and in cell cultures have shown a connection between PP2A loss of function and tau hyper-phosphorylation and aggregation into PHF.
PP2A is mainly pre- sent as a soluble protein in the cytosol but it is also encoun- tered in the nucleus, mitochondria, cytoskeleton, and mem- branes.
Furthermore, phosphorylated PP2A C decorates neurofibrillary tangles.
Within the brain, ACB55 (B55) is the major PP2A B iso- form and it binds to tau with high affinity both in in vitro protein-protein interaction paradigms and in cell cultures [36, 37].
Analyses of protein expression by using gel electrophore- sis and western blotting have shown not only a reduction of PP2A C expression levels but also a marked reduction of B55, thus indicating that PP2A impairment is the result of combined effects of different subunits [60].
So far, the most explored pathologies in which PP2A is implicated are cancer, and some viral and parasitic diseases [44]. More recently, PP2A has been investigated in FTLD linked to mutations in the tau gene [45].
Trans- genic mice with reduced PP2A activity show increased tau phosphorylation at Ser202/Thr205 and Ser42 [46].
Moreover, some tau kinases as cyclin- dependent kinase 5 (cdk5) and TPKI (thiamine pyrophos- phokinase 1)/GSK3 (glycogen synthase kinase 3) are acti- vated following PP2A inhibition in starved mice [51].
Several observations showing reduced PP2A activity by 30% in the frontal cortex in AD [55], were followed by a number of studies of PP2A mRNA and proteins.
To sum up, PP2A activity is decreased in brain of AD, as revealed by using different approaches in different laboratories.
Decreased of PP2A, but not of other phosphatases, has also been observed in Down syndrome correlating with increased tau pathology.
Car- boxyl methylation of the catalytic subunit is required for efficient in vivo assembly of the trimer C, A, and B [63-65]; a process that is balanced by the opposite actions of methyl- transferase type IV (PPMT) and the methylesterase PME-1 [66-70].
PP2A C methylation at Leu309 is reduced in AD and this seems to contribute to PP2A C dysfunction by impairing the assembly of the trimer [77, 78].
The other important post-translational modi- fication is phosphorylation of PP2A C at Tyr307 which in- hibits PP2A activity [74-76].
High levels of PP2A C phosphorylated at Tyr307 have been reported in the entorhinal cortex, hippocampus and frontal cortex in AD compared to controls [81].
Complementing these findings, immu- nohistochemical and western blot studies have shown re- duced expression of PPMT [77], and up-regulation of the PP2A inhibitors I 1 and I 2 in AD cases [79, 80].
The excessive accumulation of phosphate groups in tau is associated with its altered capacity in promoting microtubule assembly and stability [4-6].
Decreased mRNA levels of PP2A C have been reported in the CA3 region of AD hippocampus by in situ RNA hybridisation [56]. Moreover, microarray RNA analysis carried out to compare the expression of more than 7,000 gene in the amygdala, cingulate cortex, striatum and cerebellum dis- closed down-regulation of the catalytic subunit PP2A C in AD [57]. This has been further corroborated by quantitative TaqMan PCR showing reduced PP2A C mRNA expression levels in the hippocampus, but not in the frontal cortex, in AD cases with disease progression Fig. (1).
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